Proteasome-IndependentFunctions of Ubiquitin inEndocytosis and SignalingDebdyuti Mukhopadhyay and Howard Riezman*Ubiquitination is a reversible posttranslational modification of cellular proteins, in which a76–amino acid polypeptide, ubiquitin, is primarily attached to thee-amino group of lysines intarget proteins. Ubiquitination is a major player in regulating a broad host of cellular processes,including cell division, differentiation, signal transduction, protein trafficking, and qualitycontrol. Aberrations in the ubiquitination system are implicated in pathogenesis of some diseases,certain malignancies, neurodegenerative disorders, and pathologies of the inflammatoryimmune response. Here, we discuss the proteasome-independent roles of ubiquitination insignaling and endocytosis.Ubiquitin (Ub) is a highly conservedprotein of 8 kilodaltons that becomescovalently attached to lysine (Lys) res-idues of target proteins. Protein-attached Ub is asubstrate for the attachment of further Ub res-idues, which leads to the formation of a poly-ubiquitin chain. Classically, polyubiquitinationis a signal that directs proteins to the protea-some, where the Ub is recycled and the proteinis degraded (1). Ubiquitination also remodelsthe surface of substrate proteins and thereby po-tentially affects properties such as stability andactivity (2), drives interactions with other pro-teins, and plays roles in subcellular localization.Diverse forms of Ub modifications exist: Mono-ubiquitination is the attachment of a single Ub toa protein; multiubiquitination occurs when sev-eral Lys residues of the target protein are taggedwith single Ub molecules; and polyubiquitina-tion denotes the addition of a Ub chain madeof several ubiquitins that are linked throughthe C-terminal glycine residue of each Ub unitand a specific internal Lys of the previouslyattached Ub. Monoubiquitination or multiubi-quitination has been shown to be required for theentry of certain cargo proteins into vesicles atdifferentstagesofthesecretory/endocyticpathway (Fig. 1) (3), whereas polyubiquitinationhas been mainly associated with proteasomaldegradation, although it certainly has a broaderfunction (4). In the case of polyubiquitination,there can be at least seven different linkages be-tween ubiquitins, because there are seven inter-nal lysines in Ub. The role of different linkagesin polyubiquitins has begun to be elucidated inrecent years. Linkage through Lys48(UbK48) ismainly used for targeting to the proteasome, andLys63(UbK63) linkages seem to play importantroles in DNA damage tolerance, inflammatoryresponse, the endocytic pathway, and ribo-somal protein synthesis (4). Ub can also be re-moved from proteins, and different Ub hydrolasesthat regenerate free Ub have been identified andimplicated in regulation of various cellular events(5–7). Protein modules containing Ub-bindingdomains (UBDs) have also been identified andare being characterized. The identification ofmany UBDs with diverse structural folds, by

This
preview
has intentionally blurred sections.
Sign up to view the full version.